While cigarette smoking is a well-established and potent risk factor for atherosclerotic vascular disease, individual susceptibility to smoking varies considerably, suggesting modifiers such as genomic variation. Several key enzymes involved in the activation and detoxification of mutagenic tobacco smoke compounds, oxidative stress, and DNA damage are expressed in the tissues of the heart and vasculature and represent mechanistic pathways for tobacco-induced pathology. Many of these enzymes have common polymorphisms (greater than or equal too 10% prevalence in the population) with known functional effects. Although restricted to a few enzymes and hampered by shortcomings in design, a small number of studies have suggested that enzymatic activation and detoxification of tobacco smoke modifies the risk of certain cardiovascular outcomes associated with cigarette smoking. The main goal of the proposed study is to evaluate common genetic polymorphisms that, in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis and its clinical sequelae. An average of six polymorphisms, selected on the basis of their prevalence and functional significance, expression in relevant tissues, evaluation in previous studies and biologic plausibility, within 19 genes involved in activation, detoxification, oxidative stress, and DNA repair pathways will be evaluated as an ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. In this well-characterized, bi-ethnic cohort of 15,792 men and women under active follow-up since 1987-89 (completeness of follow-up 96%), five endpoints quantifying subclinical atherosclerosis and validated clinical atherosclerotic events will be studied in case-cohort/case-control mode: incident coronary heart disease, carotid atherosclerosis, peripheral arterial disease, incident stroke, and MRI-detected cerebral infarcts. The proposed investigation is well designed to study how DNA sequence polymorphisms can promote or inhibit the atherogenic effects of smoking and the risk of clinical events, and to contribute new knowledge on the role of genetic variation in the response to environmental insults and toxicants. The findings are expected to be of clinical and public health significance.